Friedel-Crafts acylation limitations

Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

The synthetic importance of the Houben-Hoesch reaction is even more limited by the fact that aryl ketones are also available by application of the Friedel-Crafts acylation reaction. 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

The exceedingly high reactivity of ferrocene to Friedel-Crafts acylation is exemplified by the fact that mild catalysts such as stannic chloride (63), boron trifluoride (32), zinc chloride (86), and phosphoric acid (29), can be used with considerable success. When ferrocene and anisole were allowed to compete for limited amounts of acetyl chloride and aluminum chloride, acetylferrocene was the sole product isolated, again illustrating the high reactivity of ferrocene toward electrophilic reagents (6). 

Friedel-Crafts acylations of the metal acetylacetonate rings are much slower than the electrophilic substitutions described above, probably because of the considerable steric bulk at the reaction site. Furthermore, the strongly acidic conditions during the reaction and subsequent hydrolysis step give rise to considerable degradation, particularly in the case of the more sensitive chromium and cobalt chelates. This consideration places severe limitations on the reaction conditions that can be employed. 

The Friedel-Crafts acylation of alkanes requires hydride abstraction, which can be induced by the acylium ion itself, to form the corresponding carbocation. This may undergo carbocationic rearrangements prior to a proton loss to form an alkene, which then reacts with the acylating agent. Similar to the acylation of alkenes, the product is an unsaturated ketone. The reaction is limited to alkanes that are prone to undergo hydride transfer. 

Thus, Friedel-Crafts acylation overcomes two of the three limitations of the alkylation The acylium ion is resonance-stabilized, so that no rearrangements occur and... 

The method is limited because of the requirement for stoichiometric reagents, but impressive applications in the preparation of complex molecules have appeared. For example, a model system for ene-diyne antibiotics has been prepared by an intramolecular route (Scheme 19). Added versatility arises from the electophilic coupling of vinyl-propargyl complexes, such as in Friedel-Crafts acylation conditions. 

In the laboratory of D.W. Cameron the total synthesis of the azaanthraquinone natural product bosttycoidin was undertaken using the Minisci reaction and the intramolecular Houben-Hoesch reaction as the key steps. It is worth noting that the synthesis of specific di- and trihydroxyazaanthraquinones by the Friedel-Crafts acylation is very limited due to the lack of orientational specificity and the lack of reactivity of pyridine derivatives in acylation reactions. 

The carbonium ion may also be formed from an alkene or alcohol. The carbonium ion formed from any of these starting materials is particularly prone to rearrangement reactions. These are called Wagner-Meerwein rearrangements, and severely limit the synthetic utility of this reaction to form simple alkyl substituted aromatic compounds. The tendency to rearrange may be reduced if the acyl derivative is used instead. This modification is called the Friedel-Crafts acylation reaction, and it has the further advantage that normally only monoacylation occurs, instead of the polyalkylation that happens using the simple Friedel-Crafts reaction. 

An impressive number of papers and books has been published and numerous patents have been registered on the aq lation of aromatic compounds over solid catalysts. Recently Sartori and Maggi [1] have written an excellent review with 267 references on the use of solid catalysts in Friedel-Crafts acylation. In one section of this review, namely acylation of aromatic ethers or thioethers, the authors report work on acylation by solid catalysts such as zeolites, clays, metal oxides, acid-treated metal oxides, heteropolyacids or Nafion. When examining in details these results, it appeared very difficult for us to build upon these experimental results as the reaction conditions differ drastically from one paper to the next. This prompted us to reinvestigate the scope and limitations of the Friedel-Crafts acylation using heterogeneous solids as catalysts, trying as much as we could to rationalize the observed effects. 

Murakami, Y, Tani, M., Ariyasu, T., Nishiyama, C., Watanabe, T., and Yokoyama, Y, The Friedel-Crafts acylation of ethyl pyrrole-2-carboxylate. Scope, limitations, and apphcation to synthesis of 7-substituted indoles, Hetemcycles, 27, 1855, 1988. 

When examining in detail these results it appeared very difficult for us to build upon these experimental results as the reaction condition differ drastically from one paper to the other. This prompted us to reinvestigate the scope and limitation of the Friedel-Crafts acylation using heterogeneous solid as catalysts in trying as much as we could to rationalized the observed effects. 

Acyl halides bearing a-hydrogen atoms, and acetyl chloride in particular, have limited stability in the presence of strong Lewis acids. Elimination of proton from the acylium ion leads to the ketene. This intermediate undergoes ready Friedel-Crafts acylation, acetyl chloride eventually forming the diacetylace-tylium ion, ° which is a poor acylating agent. For this reason, excessive reaction temperatures and times should be avoided in Friedel-Crafts acetylations. 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

The use of Y, BEA, and ZSM-5 zeolites in the Friedel-Crafts acylation of aromatics shows some limitations when large-sized molecules are utilized. In fact, because of the dimension of their pores, the access to the internal active sites of these zeolites is restricted to molecules with kinetic diameter up to 8 A. Trying to overcome this drawback, mesoporous molecular sieve MCM-41 can be utilized as interesting catalyst or support for catalysts for reactions involving larger molecules. 

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